1、MyopathiesDepartment of NeurologyTongji HospitalEmail:Min ZhangCase 1 21 years old,female patient Progressive generalized muscle weakness for 8 years The patient began to notice weakness in the hips and increasing difficulty in arising 8 years ago.Six months later the weakness advanced to the knees
2、and she could arise only by climbing up her legs.”Twelve months later,she felt extreme weakness in her shoulders and upper arms so that she gradually became unable to comb her hair or even lift her arms to shoulder level.Case 1 Difficulty of locomotion slowly became more pronounced until at the time
3、 of admission.There were never any symptoms of tremor,spasticity,sensory or sphincter disturbances.No history of similar disease in her family.Case 1 Marked atrophy of the shoulder girdle and thighs,winged scapula and waddling gait.Tendon reflexes decreased bilaterally.No impairment of superficial a
4、nd deep sensibility.CK 13503 u/LDiagnosis?Introduction Myology Common diseases Affecting all ages Complexity of pathogenesis New diseases to be identifiedCommon manifestations Weakness Atrophy Pseudohypertrophy Myalgia(muscle pain)and cramp Fatigability Topography of myopathic weakness Ocular palsy:
5、ptosis,diplopia,strabismus Bifacial palsy:smile,expose the teeth,close the eyes Bulbar palsy:dysphonia,dysarthria,dysphagia Cervical palsy:hold the head erect,lift the head from the pillow Weakness of respiratory and trunk muscleTopography of myopathic weakness Bibrachial palsy:hands,arms,shoulders
6、Bicrural palsy:lower leg weakness,inability to walk on the toes/heels Limb-girdle palsy:inability to raise the arms or arise from squatting,kneeling or sitting position Distal bilateral limb palsy:foot drop General paralysisChanges of muscle bulk Myalgia and cramp Spontaneous，symmetrical，proximal Se
7、vere pain:Cramp Over exercise Metabolic factors:hypocalcaemia,glycogen storage disease Medication:Statin,Captopril MyotoniaCommon myopathies Muscular dystrophies Inflammatory myopathies Disorders of neuromuscular junction Metabolic myopathies Endocrine myopathies Toxic myopathies Others Progressive
8、muscular dystrophiesBasic concept Hereditary myopathies Heterogeneity:diversity of gene mutations and presentations Muscular degeneration No effective treatment availableClassification of PMDX-linked:Duchenne muscular dystrophy(DMD)Becker muscular dystrophy(BMD)Emery-Dreifuss muscular dystrophy(EDMD
9、)Autosomal dominant:Facioscapulohumeral muscular dystrophy(FSHMD)Myotonic dystrophy Distal muscular dystrophy Oculopharyngeal muscular dystrophy Congenital muscular dystrophyAutosomal rescessive:Limb-girdle muscular dystrophy(LGMD)Congenital muscular dystrophyMuscular degeneration Progressive muscul
10、ar necrosis Increases in CK and LDH Fat infiltration of muscles Limited regeneration of myofibers No inflammatory responseNormal muscleDegeneration and regenerationDuchenne muscular dystrophy X-linked,recessive The most common and severe Gene defects：dystrophin gene Lack of dystrophin Muscular degen
11、eration Dystrophin expressions a:normalb:BMDc:DMDd:carrier Clinical presentations(1)Boys affected Age at onset:2-5 yrs Symptoms:frequent falling weakness of limb-girdles Clinical presentations(2)Signs:pseudohypertrophy of calves muscle weakness of girdles:Gowers sign Waddling gait Winged scapula Har
12、d to walk with heelPseudohypertrophy Winged scapula Gowers sign Needing hands when standing from supine position,because of pelvic-girdle weaknessGowers signClinical presentations(3)EKG abnormalities Seral enzymes:10100 fold increases in LDH and CK EMG:myopathic(low amp.,poly-phasic APs)Biopsy:muscu
13、lar degeneration regenerationDMD Biopsy 1DMD Biopsy 2Diagnosis Family history Clinical manifestation Enzymes EMG Biopsy Dystrophin IHC，genetic testingCourse and prognosis Onset:25 yrs Bedridden:1220 yrs Die:1820 yrsGenetic consultations Female:carrier Male siblings:have chance to be the suffers Fema
14、le siblings:,carrierTreatment Glucocorticoids significantly slow progression of DMD up to 3 yrs.Gene therapyGene therapy dystrophin gene vector animal models(mdx)evaluation Introduction of dystrophin geneCase 1 21 years old,female patient Progressive generalized muscle weakness for 8 years The patie
15、nt began to notice weakness in the hips and increasing difficulty in arising 8 years ago.Six months later the weakness advanced to the knees and she could arise only by climbing up her legs.”Twelve months later,she felt extreme weakness in her shoulders and upper arms so that she gradually became un
16、able to comb her hair or even lift her arms to shoulder level.Case 1 Difficulty of locomotion slowly became more pronounced until at the time of admission.There were never any symptoms of tremor,spasticity,sensory or sphincter disturbances.No history of similar disease in her family.Case 1 Marked at
17、rophy of the shoulder girdle and thighs,winged scapula and waddling gait.Tendon reflexes decreased bilaterally.No impairment of superficial and deep sensibility.CK 13503 u/LDiagnosis?Inflammatory myopathiesCase 2 male，68 years old.Progressive weakness of limbs,accompanied by atrophy for 2 years.EMG:
18、myopathic pattern.Muscle enzymes:CK:3500u/L.Muscle biopsy：profound necrosis,regeneration and inflammatory cell infiltration.Diagnosis：?Treatment：?Different forms of inflammatory myopathies Infective:Parasitic:Trichinosis Toxoplasmosis Fungal Viral Idiopathic Common idiopathic inflammatory myopathies
19、 Dermatomyositis（DM）Polymyositis（PM）Inclusion body myositis Other immunological related myositis Eosinophilic fasciitisPM and DM PM：inflammation restricts in striate muscle DM：accompanied by skin lesion Different at immunological process and pathologyPM and DM Idiopathic Subacute or chronic Symmetri
20、cal Weakness Proximal limb and trunk muscles Dermatomyositis:with dermatitisEtiology and pathogenesis Unknown Infection Autoimmune mechanism:DM:CIC,IgG,IgM,C3 and membrane-attack complexes are deposited in the walls of vessels PM:CD8,MHC-1Common clinical features Onset:usually insidious,preceding hi
21、story Subacute or chronic The course progressive over a period of several weeks or months Symmetrical weakness Proximal limb and trunk muscles Neck,larynpharyngeal muscles Respiratory muscles can be involved in severe cases No involvment of extraocular muscles Common clinical features Impairment of
22、other organs:Cardiac abnormalities：sudden death Myocarditis Arrhythmia Interstitial pneumoniaSkin lesions of DM Skin lesion usually preexisted weakness Forms of expression：dermatitis Localized or diffused erythema Maculopapular eruption(斑丘疹)Scaling eczematoid dermatitis(脱屑性湿疹样皮炎)Exfoliative dermatit
23、is(剥脱性皮炎）Features：Patches of a scaly roughness over the extensor surfaces of joints;Heliotrope changes in skin over eyelid,cheeks and forehead.Photosensitivity:V sign;Shawl sign Maybe transient Skin lesions of DMRed,raised papules presented over exposed surface such as distal and proximal Interphala
24、ngeal joint:Gottrons papulesOther features of DM Periarticular and subcutaneous calcifications Concurrent connective tissue disease The Raynaud phenomenon SclerodermaSpecial forms of DM DM of childhood Concurrent CTD Concurrent carcinoma:lung and colon cancer in men breast and ovarian cancer in wome
25、n NPC DM of childhood A distinctive syndrome Intermittent low-grade fever A greater involvement of blood vessels Acute gastric or enteric perforation CREST Calcinosis Raynaud phenomenon esophageal involvement sclerodactyly（指趾硬皮病）telangiectasia（毛细血管扩张）Concurrent CTDRheumatoid arthritisSclerodermaLupu
26、s erythematosusMixed CTDSjgren syndromeCo-occurrence of MGHashimoto thyroiditisConcurrent Carcinoma Lung and colon cancer in men Breast and ovarian cancer in women Antedates the clinical manifestations of the malignancy,sometimes by 1 to 2 or more years Occasionally,excision of the tumor is attended
27、 by remission of the myositisPhysical examination Usually not tender Weakness，atrophy Reduction in tendon reflexes Fibrous contracture Skin lesionInvestigation Muscle enzymes:CK,LDH,GOT The increase is more markedly in PM Can be used to observe the effect of treatments ESR EMG:myopathic patternMRIAb
28、normalities in T1and T2 signal intensity define regions of increased water content and inflammation in muscleAutoantibodies Anti-component of muscle fibre:anti-Jo1:interstitial pneumonia anti-SRP:severe PM anti-Mi-2：DM P-155：adolescent DM Non-specific antibodies:Antibodies for CTD:ANA,RF,SS-A/BInves
29、tigationMuscle biopsy:Widespread degeneration,regeneration Inflammatory reaction Tubular aggregates in the endothelial cytoplasm occlusion of vessels by fibrin thrombi DM:perifascicular muscle fiber atrophy PM：IHC:MHC-1 and CD8(+)Biopsy 1Biopsy 2Biopsy 3Biopsy 4MHC-1 immunohistochemical stainingBiop
30、sy 5Investigation ECG Carcinoma Screening:C-12:specific markers of tumors X-ray or CTDiagnostic criteria of PM1.Myopathic weakness,which:evolves over weeks to months spares facial and eye muscles is manifested in patients above the age of 18 yearsDalakas MC,Hohlfeld R.Diagnostic criteria for polymyo
31、sitis and dermatomyositis.Lancet 2003;362:17621763Diagnostic criteria of PM2.Patient DOES NOT have:rash,characteristic of dermatomyositis a family history of neuromuscular diseases exposure to myotoxic drugs,(D-pencillamine,zidovudine,statins)endocrine disease(hypothyroid,hyperthyroid,hypoparathyroi
32、d,hypercortisolism)neurogenic disease(excluded by electromyogram and neurological examination)dystrophies and metabolic myopathies(excluded by history and muscle biopsy)IBM(excluded by clinical examination and muscle biopsy)Diagnostic criteria of PM3.Disease can be associated with:another autoimmune
33、 disease or viral infection4.Polymyositis is rare as a stand-alone entity Diagnostic criteria of PM5.Reconsider polymyositis if:disease onset below the age of 18 years myopathy has slow onset and evolves over months to years(in such cases think of IBM or dystrophy)patient has fatigue and myalgia,wit
34、hout muscle weakness,even if a transient CK elevation is seen(such patients may have fibromyalgia or fasciitis and their muscle biopsy is either normal or non-specific)there are no typical histological features of polymyositis,especially when there is an absence of MHC-I or MHC-I/CD8 complex Differe
35、ntial diagnosis Hereditary myopathies Duchenne dystrophy facioscapulohumeral dystrophy limb-girdle dystrophy IBM Drug induced myopathiesTreatment Corticosteroids：first line IVIG:DM,no responds to corticosteroids Other immunosuppressant:refractory or cannot tolerate Azathioprine Methotrexate Cyclopho
36、sphamideTreatment Prednisone：1mg/kg/d Carefully monitor by testing of strength and measurement of CK After 4-6w，recovery begin,reduce the dosage gradually Caution reduce to 10-20mg/d over a period of 6m to 1 year Discontinuation of the drug:treatment2 years muscle enzymes and strength back to normal
37、Prognosis Adult:most porpotion favorable 20%:recovery Early treatment and acute onset:50%remission Poor prognosis:concurrent malignancy,CTD,Children Mortality:15%Case male，68 years old.Progressive weakness of limbs,accompanied by atrophy for 2 years.EMG:myopathic pattern.Muscle enzymes:CK:3500u/L.Mu
38、scle biopsy：profound necrosis,regeneration and inflammatory cell infiltration.Investigations?Diagnosis：?Differential diagnosis?Treatment：?Inclusion body myopathy The 3rd major form of idiopathic inflammatory myopathy Over 1/3 of cases of inflammatory myopathy are of this type.Predominates in males(i
39、n a ratio of 3:1)Onset in middle or late adult life Sporadic or inheritedClinical manifestation Painless muscular weakness and atrophy Often asymmetrically Selective weakness of flexor pollicis（拇长屈肌）or Longus（伸肌）,quadriceps,and neck extensor。Steadily progressive 20%sporatic cases associated with Dia
40、betes,CTD or mild polyneuropathyClinical manifestationInvestigations Muscle enzymes:normal or slightly elevated lower levels than in cases of PM EMG:myopathic pattern a small proportion display a more frankly neuropathicBiopsy Identical to but usually of lesser severity than those observed in PM Rim
41、med vacuoles（镶边空泡）Inclusion body：eosinophilic inclusions in both the cytoplasm and nuclei congophilic:stain positively for AInflammatory reactionInfiltration of monocyteRVs，HERVs，GomoriDiagnosis Clinical manifestation Muscle biopsy：inflammation，RVs Staining：Congo-red，SMI-31,tau，Abeta，Ubiquitin,etc E
42、lectron microscopeRelentlessly progressiveEosinophilic Fasciitis Predominates in male Appear 30-60 years Symptom：low-grade fever，myalgia，diffuse cutaneous thickening and limitation of movement of small and large joints Signs:Scleroderma-like appearance of the skin and flexion contractures at the kne
43、es and elbows Eosinophilic Fasciitis Elevated ESR and eosinophilia MRI:Thickened fascia Skin and muscle biopsy:Thickened fascia Plasma cells,lymphocytes,eosinophil infiltrate Normal muscle fibers Skin lacked the characteristic histologic changes of sclerodermaTreatment Remits spontaneously Responds
44、well to corticosteroidsDiseases of neuromuscular junctionNMJCase 女性，25岁 右上睑下垂，伴视物成双2月。既往有“甲亢”史。体检：右上睑下垂，双瞳孔等大等园，光反射存在，右眼球 外展受限。无其他神经系统阳性体征。眼科检查：视力、眼底正常。诊断？肌肉注射“药物”20分钟后完全缓解，60分钟后症状再发。Acetylcholine receptor Diseases of NMJ Myasthenia gravis:AchR decrease Eaton-Lambert syndrome Congenital myasthenia：m
45、utations in AChR genes Neurotoxins:black widow:enhance Ach release botulinum toxin:block Ach release alpha-bungarotoxin:bind to AchRFemale black widows Impairment of NMJalpha-bungarotoxinEaton-LambertBlack widow(+)MGbotulinum(-)Case 3 Female,25yrs Dropping of the right eyelid and double vision for 2
46、m.Past history:Hyperthyroidism PE：Ptosis on the right side.Pupils are normal.Limitation of the abduction of eye ball.Visual acuity and fundus are normal.Treatment:intramuscular injection of“some medication”Prognosis:complete remission after 20mins reoccurrence after 60minsMyasthenia Gravis(MG)Myasth
47、enia gravis(MG)Incidence:5/100,000 Autoimmune disease Decrease in AChR on the end-plate Impaired neuromuscular transmissionPathophysiology Antibodies,to alpha subunit of AChR Blocking or degradation of AChR Signal transduction damaged Weakness and fatigability nervenervemusclemuscleAnimal models Exp
48、erimental autoimmune myasthenia gravis(EAMG)Purify AChR from Torpedo electroplax Immunize animals with AChR plus adjuvant Assessment:clinical,immunologic and electrophysiologic Torpedo electroplaxEAMG and neostigminePathologic roles of AChR-ab Cross-linking with Abs Increase in endocytosis and turn-
49、over of AChRs Activation of complement pathwaysMyopathology Simplification of post-synaptic folders Widening of folders Decrease in AChR by 90%Deposits of complements at the end-platesClinical findings（1）Age:children,40-50%Gender:1：11.5(M:F)Characteristics pathologic fatigability Mode of onset:chron
50、ically fluctuating05101520253035404550556065707501020304050FemalesMalesAge at presentationNumber of patientsClinical findings（2）Ocular:ptosis,diplopia Clinical findings（2）Facial:myopathic expression Masseter:difficulty chowing Bulbar:dysphagia,dysarthria Neck muscles:difficulty raising head Extremit
